Hemodynamic effects of KRN2391 (potassium channel opener) in halothane-anesthetized dogs.

The cardiovascular responses to an infusion of KRN2391, a potassium channel opener, was studied in halothane-anesthetized dogs. Intravenous administration of KRN2391 at 1.0 and 5.

[Herpes zoster of the right cervical region associated with right facial nerve palsy and hoarseness].

A 69-year-old man was suffering from herpes zoster on his 2nd and 3rd right cervical spinal segments and 3rd branch of the trigeminal nerve. He came to our hospital on his 10th illness day and was treated with continuous cervical epidural block, intravenous infusion of acyclovir for five days, and oral paramethasone and Vitamin B12. Oh his 18th illness day, right facial nerve palsy and hoarseness became clear.

[Endocrine effects of induced hypotension by ketanserin in anesthetized dogs].

Plasma levels of catecholamines, aldosterone and cortisol as well as plasma renin activity during hypotension by ketanserin were studied in 9 mongrel dogs under 0.87% halothane in oxygen (1MAC). Mean arterial pressure was reduced and maintained at 60 mmHg for 60 minutes by the infusion of 0.

[Hemodynamic effects of induced hypotension by ketanserin in anesthetized dogs].

Hemodynamic effects of hypotension induced by ketanserin were investigated in 18 mongrel dogs under 0.87% halothane in oxygen (1 MAC). They were randomly allocated to one of two groups.

[Endocrine effects of hypotension induced by diltiazem in rabbits].

Endocrine effects of hypotension induced by diltiazem, a calcium antagonist, were studied in 16 male rabbits under the inhalation of 0.7% halothane in oxygen. They were randomly allocated to one of two groups.

[A comparison of the endocrine effects of hypotension induced by nicardipine with those by sodium nitroprusside in dogs].

Plasma catecholamines, plasma renin activity, plasma aldosterone and plasma cortisol during hypotension induced by sodium nitroprusside and nicardipine were studied in 27 mongrel dogs under 0.87% halothane in oxygen. They were randomly divided into three groups: sodium nitroprusside (group S: n = 8), nicardipine (group N: n = 8) and controls (group C: n = 9).

Identification of benidipine hydrochloride metabolites in rats and dogs.

A study of the metabolism of [14C]-(+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)- 1,4-dihydropyridine-3, 5- dicarboxylic acid (R*)-1-benzyl-3-piperdidinyl ester, methyl ester hydrochloride (14C-benidipine hydrochloride, 14C-KW-3049) revealed as major metabolic pathways oxidative N-dealkylation, hydrolysis of the ester moiety, dehydrogenation of the 1,4-dihydropyridine ring, hydroxylation of the methyl group and decarboxylation in rat and dog. Rat and dog showed similar metabolic pathways, but some quantitative differences were found between rat and dog.

Pharmacokinetic study of benidipine hydrochloride in rats and dogs.

(+/-) - (R*) - 2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine - 3, 5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) is presently under development as an anti-hypertensive and antianginal agent. A pharmacokinetic study in rat and dog after oral and intravenous administrations revealed that KW-3049 was rapidly absorbed from the gastrointestinal tract, distributed into tissues moderately and comparatively quickly eliminated. After oral administration, non-linearity of bioavailability with increment of doses was observed in both rat and dog.

Absorption, distribution and excretion of 14C-benidipine hydrochloride after repeated administration to rats.

The absorption, distribution and excretion of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) were studied after repeated doses to rats. The results were summarized as follows: 1. After oral repeated administration once a day for 3 weeks, the radioactivities in blood and tissues increased up to the 14th day, and thereafter they tended to show the steady state.

Absorption, distribution and excretion after oral administration of 14C-benidipine hydrochloride in rats and dogs.

(+/-)-(R*)-2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5- dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) has been developed as antihypertensive and antianginal agent. The absorption, distribution and excretion were investigated after single oral administration of 14C-labeled KW-3049 using Wistar rats and beagle dogs. The results were summarized as follows: 1.

Determination of the calcium antagonist benidipine hydrochloride in plasma by sensitive radioimmunoassay.

A sensitive radioimmunoassay of the 1,4-dihydropyridine calcium channel blocker (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) has been developed. Antiserum against KW-3049 was produced in rabbits by immunization with an immunogen prepared by conjugating a derivative of KW-3049 to bovine serum albumin. This antiserum was found to specifically bind to [3H]-KW 3049, while the recognition to [3H]-nitrendipine, another well-known dihydropyridine calcium channel blocker, was less pronounced.

Sensitive radioreceptor assay of the calcium antagonist benidipine hydrochloride in plasma and urine.

Plasma and urinary concentrations of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) were measured by the radioreceptor assay using 3H-nitrendipine and rat cardiac membrane receptor. After methanol deproteinization and ethyl ether extraction under alkaline conditions as pretreatment, the detection limit for KW-3049 in plasma was 0.2 ng/ml using 0.

Gas chromatographic method for the quantification of the new calcium antagonist benidipine hydrochloride in plasma using electron capture detection.

A gas chromatographic assay procedure was developed for measuring subnanogram order concentrations of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5- dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) in plasma. KW-3049 yielded the oxidation product partially during gas chromatography. To avoid decomposition, KW-3049 was oxidized in advance by nitrogen dioxide, extracted by diethylether under alkaline condition, chromatographed on the OV-1 column and measured using electron capture detector.

Pharmacological actions of benidipine hydrochloride in several isolated smooth muscles and myocardium.

Using various isolated smooth muscles and myocardium, the calcium antagonistic effect of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049), and its specificity were examined. Furthermore, the in vitro duration of action and the antispasmodic actions in coronary arteries were investigated in comparison with those of nifedipine, verapamil and diltiazem. 1.

Beneficial effects of the new calcium antagonist benidipine hydrochloride on myocardial dysfunction following coronary occlusion and reperfusion in anesthetized dogs.

The protective effect of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1, 4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) on ischemic myocardium was examined comparing with that of nifedipine in anesthetized dogs subjected to a brief (10 min) coronary artery occlusion and reperfusion (2h). Occlusion of left anterior descending coronary artery elicited elevation of ST-segment and T-wave of epicardial ECG in the ischemic area. Regional myocardial contractile force in this area was depressed throughout the reperfusion period as well as during coronary occlusion period.

Effects of the new calcium antagonist benidipine hydrochloride on cardiohemodynamics in anesthetized dogs.

The effects of (+/-)-(R*)-2,6-dimethyl-4-(m-nitro-phenyl)-1,4-dihydropyridine -3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinylester, methylester hydrochloride (benidipine hydrochloride, KW-3049) on the cardiohemodynamics were investigated in open-chest, anesthetized dogs, in comparison with those of nifedipine. When KW-3049 at a dose of 3 micrograms/kg was intravenously administered, hypotensive action (delta dBP = -20 mmHg) with a peak attained 3 to 5 min after the administration was observed and its action lasted for 2 h or more. Simultaneously, a slight decrease of heart rate and continuous increases of LV max dp/dt and cardiac output were recognized.

Vasodilating effects of the new calcium antagonist benidipine hydrochloride in anesthetized dogs and cats.

Vasodilating effects of a new 1,4-dihydropyridine derivative, (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3, 5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) were investigated in anesthetized dogs and cats. Intravenous administrations of KW-3049 at doses of 0.3 to 10 micrograms/kg exhibited a greater vasodilation in vertebral and coronary arteries than in common carotid and femoral arteries.

Antianginal effects of the new calcium antagonist benidipine hydrochloride in anesthetized rats and spontaneously hypertensive rats. Electrocardiographic study.

Antianginal effects of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) in various experimental angina-pectoris models (anesthetized rats, spontaneously hypertensive rats (SHR] were compared with those of nifedipine, propranolol and hydralazine. Furthermore, the effects of these drugs on the pressure-rate product were evaluated. 1.

Effects of benidipine hydrochloride on atrioventricular conduction time and postural reflex in gallamine-immobilized cats.

Using gallamine-immobilized cats, the effect of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dic arb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) was compared with those of other drugs in terms of the propensity for atrioventricular conduction disturbances and orthostatic hypotension. The administration of KW-3049 at doses of 1 to 300 micrograms/kg i.v.

Antihypertensive effects of the new calcium antagonist benidipine hydrochloride in conscious, renal-hypertensive dogs.

The antihypertensive action of (+/-)-(R*)-2,6-dimethyl-4- (m-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) was evaluated in conscious, renal-hypertensive dogs. When KW-3049 (0.1, 0.

Antihypertensive effects of intravenous administration of benidipine hydrochloride and some other calcium antagonists in conscious, spontaneously hypertensive rats.

The antihypertensive effect of intravenously administered (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) was examined in conscious, spontaneously hypertensive rats (SHR) and comparatively evaluated with those of nifedipine, nicardipine, nitrendipine, nisoldipine, verapamil and diltiazem. When nifedipine (10 and 100 micrograms/kg), nicardipine (10 and 100 micrograms/kg), nitrendipine (10 and 100 micrograms/kg), verapamil (100 and 1000 micrograms/kg) and diltiazem (100 and 1000 micrograms/kg) were intravenously administered to SHR, at their lower doses, only transient decreases of blood pressure were observed and, even at their higher doses, decreased blood pressures returned to the initial levels after 80 to 120 min. Nisoldipine at 10 micrograms/kg (i.

Slow dissociation of the new slow-onset and long-acting calcium antagonist benidipine hydrochloride from 3H-nitrendipine binding sites.

The dissociation rates of (+/-)-(R*)-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarb oxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049) and some calcium antagonists from 3H-nitrendipine binding sites were studied by a centrifugation technique and a filter-absorbed tissue method. KW-3049 dissociated from 3H-nitrendipine binding sites more slowly than other calcium antagonist, namely nifedipine, nitrendipine, nilvadipine, nicardipine and nisoldipine. The slow dissociation of KW-3049 from 3H-nitrendipine binding sites was supported by the equilibrium binding studies.

Physico-chemical properties and stabilities of the highly potent calcium antagonist benidipine hydrochloride.

(+/-)-(R*)-2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3, 5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049), a highly potent calcium antagonist, was examined to clarify its physico-chemical properties, i.e. melting point, spectra (UV, IR, NMR, MS), X-ray diffraction pattern, thermal analysis, solubilities, pKá, partition coefficient and chromatography (TLC, HPLC).

Synthesis of expected metabolites of benidipine hydrochloride.

(+/-)-(R*)-2,6-Dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3, 5-dicarboxylic acid (R*)-1-benzyl-3-piperidinyl ester, methyl ester hydrochloride (benidipine hydrochloride, KW-3049, 1), a highly potent and long-acting calcium antagonistic 1,4-dihydropyridine derivative, is now under clinical study as an antihypertensive and as an antianginal agent. In order to confirm the structures of the metabolites of KW-3049, 19 compounds were prepared. Among them 11 compounds were found to be metabolites (the compounds 2, 3, 6, 8, 14, 15, 16, 28, 31, 32 and 34) of KW-3049 in rats and/or dogs.

Synthesis and pharmacological activity of stereoisomers of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxylic acid methyl 1-(phenylmethyl)-3-piperidinyl ester.

1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic++ + acid methyl 1-(phenylmethyl)-3-piperidinyl ester 1, a highly potent calcium antagonist, was separated into stereo- and optical isomers to investigate the differences of antihypertensive activities between them. Fractional crystallization of the hydrochlorides of 1 gave alpha- and beta-diastereoisomers. The alpha-isomer (benidipine hydrochloride, KW-3049) showed very strong hypotensive effect, but little activity was observed in the beta-isomer.